Chemoanatomic changes associated with aging in vestibulo-sympathetic pathways

描述（由申请人提供）：前庭系统检测到身体位置和姿势的变化，通常伴随着血压的快速变化。这些代偿性调整，使人类能够站起来而不晕厥，是由前庭系统的功能整合和尾侧髓网状形成中的血压控制机制介导的：来自前庭耳石器官的信号为较短潜伏期的前庭交感神经反射（VSR）提供主要输入来源，而动脉压力感受器通过相对较长潜伏期的压力反射调节交感神经张力。尽管临床文献一直报道前庭自主神经功能随着年龄的增长而下降，并且这种下降与老年人跌倒风险增加和死亡率增加有关，但这种功能丧失背后的细胞机制尚不清楚。这项为期两年的探索性项目的总体目标是确定老年啮齿动物关键尾侧脑干部位的化学解剖学变化，这些变化与VSR和压力反射功能的评估相关。两个具体目标是：(1)获得自主神经活动的生理测量，特别是心率和血压(a)基线条件下，(b)对压力反射激活的反应，(c)对年轻成年和老年大鼠和小鼠前庭刺激的反应；(2)在青年和老年大鼠和小鼠中观察三种条件下Aim 1激活的Fos蛋白及其在髓质区域的递质和调节剂表达。本研究将评估总体假设，即尾髓质化学解剖结构的特定改变与VSR的年龄依赖性下降和血压的压力反射控制平行。该项目还将评估两种常见的啮齿动物衰老模型在前庭自主神经结构和功能研究中的效用。

DESCRIPTION (provided by applicant): Changes in body position and posture are detected by the vestibular system and are normally accompanied by rapid modifications in blood pressure. These compensatory adjustments, which allow humans to stand up without fainting, are mediated by functional integration of the vestibular system and blood pressure control mechanisms in the caudal medullary reticular formation: signals from the vestibular otolith organs provide the primary source of input to the shorter latency vestibulo-sympathetic reflex (VSR), while arterial baroreceptors regulate sympathetic tone via the relatively long- latency baroreflex. Although the clinical literature has consistently reported a decline in vestibulo-autonomic function with age, and this decline is associated with increased risk of falling and increased mortality in older people, the cellular mechanisms underlying this loss of function are not known. The overall goal of this two-year exploratory project is to identify chemoanatomic alterations in key caudal brainstem sites of aged rodents, correlated with assessment of VSR and baroreflex function. The two specific aims are (1) to obtain physiological measures of autonomic activity, particularly heart rate and blood pressure (a) under baseline conditions, (b) in response to baroreflex activation and (c) in response to vestibular stimulation in young-adult and aged rats and mice; and (2) to visualize Fos protein, and transmitter and modulator expression in medullary regions activated by the three conditions of Aim 1, in young adult and aged rats and mice. This research will evaluate the overall hypothesis that specific alterations in the chemical anatomy of the caudal medulla parallel an age-dependent decline in VSR and baroreflex control of blood pressure. The project will also assess the utility of two common rodent models of aging for studies of vestibulo-autonomic structure and function. PUBLIC HEALTH RELEVANCE: Rapid adjustments in blood pressure normally accompany movements and changes in body position and posture; these compensatory adjustments allow humans to stand up without fainting. Orthostatic hypotension, which is highly prevalent in the elderly, occurs when the vestibulo-sympathetic reflex fails to mediate such compensatory adjustments. This project will evaluate the hypothesis that specific alterations in the chemical anatomy of the caudal medulla parallel an age-dependent decline in vestibulo-sympathetic- and baroreflex control of blood pressure, thereby suggesting new pharmacotherapies to ameliorate orthostatic hypotension and more specific anti-hypertensive medications that do not elicit disabling vestibular side effects such as dizziness and vertigo.